Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs weakens amygdala responses. We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last.
Neutral, fearful, and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs.
These results suggest fundamental differences in these treatments’ therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, it is now proposed that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions.
Introduction
Psychedelic therapy is a re-emerging paradigm in psychiatry. Unlike other, psychopharmacological treatment models that seek to medicate patients on a chronic basis, the psychedelic model seeks to treat core psychological issues via a small number of profound and potentially transformative psychological experiences. Our recent open-label study of psilocybin with psychological support for treatment-resistant depression (TRD) yielded promising results, with all patients showing some reduction in depressive symptoms at 1 week and half meeting criteria for remission at 3 weeks.
Furthermore, other clinical studies with psilocybin have found reductions in anxiety and depressive symptoms after psilocybin with psychological support.
Psilocybin, a classic psychedelic, and non-selective serotonin 2A receptor (5-HT2AR) agonist, was discovered and marketed in the 1950’s and 60’s. After much early enthusiasm about the therapeutic potential of psychedelics, a politically-led about-turn in the mid-1960s and early 1970s effectively ended all research with these drugs, and it has only been in the last 10-15 years that clinical researchers have begun to work with them again. During this renascent period, impressive results have been found for the treatment of depression, end of life anxiety and addiction.
The amygdala has previously been implicated in the pathophysiology of depression as well as the action of some antidepressants and psychedelics. The amygdala is a complex subcortical structure that is sensitive to emotional stimuli. Functional MRI studies of untreated clinically depressed patients have found amygdala hyper-sensitivity to negative emotional stimuli, and treatment with SSRI has been found to attenuate this; both with chronic SSRI-use as well as early in treatment, prior to the appearance of clinical improvements.
Here, we sought to explore the antidepressant action of psilocybin on amygdala responses to emotional faces using a functional magnetic resonance imaging (fMRI) paradigm that has been well-validated in the context of SSRI-based treatments for depression. Patients underwent balanced versions of an emotional face’s paradigm before and one-day after treatment with psilocybin. Psilocybin has been found to be associated with improved mood in the sub-acute period days after exposure. We therefore predicted that amygdala responses to emotional faces would be altered post-treatment and that this might relate to changes in depression severity. We were particularly interested in the fearful versus neutral faces contrast, due to previous findings of reduced amygdala responses to negative emotional stimuli with SSRI’s. We also predicted that the nature of the acute psychological experience under psilocybin would relate to the post-treatment changes in amygdala responses.
Key Findings & Overview
Increased amygdala responses to emotional faces were observed one day after treatment with psilocybin for treatment-resistant depression. Post-treatment increases in amygdala responses to fearful versus neutral faces were related to a successful clinical outcome one week later.
Importantly, the present findings are in contrast to observations of decreased amygdala responses after treatment with conventional antidepressants and particularly with SSRI’s. It has been proposed that decreased amygdala responsiveness to negative emotional stimuli under SSRIs is a key component of their therapeutic action, but the present study’s findings suggest that this model does not extend to the therapeutic action of psilocybin for TRD.
Observations of reduced amygdala responses to negative emotional stimuli and reduced behavioral response biases to negative stimuli with conventional antidepressants have been interpreted as evidence of a functional remediation, linked to the correcting of negative cognitive biases in depression. However, it is suggested that chronically used antidepressants have a more generalized effect on emotional processing, moderating not just responsiveness to negative emotional stimuli, but emotional stimuli more broadly. Focusing specifically on the amygdala, this structure is known to be generally sensitive to emotional salience, regardless of the emotional valence of the stimuli. It is possible that the notion that SSRIs have a selective action on amygdala responses to negative stimuli is fallible, and rather, SSRIs and related antidepressants have a more generalized muting influence on amygdala responses to emotionally salient stimuli. Relatedly, negative stimuli may be processed as especially salient, and thus be associated with greater amygdala responses which are subsequently hyper-sensitive to intervention-led change.
Reduced amygdala responses to emotional stimuli after chronic antidepressant medication has been linked with activation of post-synaptic serotonin 1A receptors (5-HT1ARs), which have an inhibitory action on pyramidal cell firing and are densely expressed in the amygdala. While this mechanism has a solid empirical basis, there is no known mechanism to explain how 5-HT1AR-induced attenuation of amygdala responsiveness can selectively apply to negative stimuli, without simultaneously affecting the processing of positive stimuli of an equivalent salience. Indeed, there is evidence of blunting of positive mood with SSRI’s. Moreover, the relative ineffectiveness of conventional serotonergic antidepressant medications to alleviate anhedonia (decreased ability to feel pleasure) may be explained by a generalized moderation of emotional responsiveness with these drugs.
We recently carried out a qualitative analysis of patient experiences from this clinical trial, asking patients whether psilocybin with psychological support has been effective for them, and if so, how? Since many patients reported improvements with the treatment, most answered in the affirmative and described a greater willingness to accept all emotions post-treatment (including negative ones). These effects were often contrasted with those of their previous depression treatments which they described as working to reinforce emotional avoidance and disconnection. Conversely, psilocybin was said to make emotional confrontation more likely, and the accompanying psychological support helped patients achieve an emotional breakthrough (catharsis) and resolution. Consistently, recent work has suggested that overcoming challenging emotional phenomena under a psychedelic is predictive of better long-term mental health outcomes.
Future Implications
Psilocybin represents a novel intervention for major depression that appears to be safe, rapid, and potentially enduring in its antidepressant action. Furthermore, it is important to note that psilocybin’s abuse potential is low. The original rationale for using psychedelic (mind-revealing) drugs as aides to psychotherapy was that they serve to dismantle psychological defences, allowing suppressed emotional material to surface, sometimes with cathartic effect.
The present findings of increased amygdala responsiveness post psilocybin resonate with patients’ descriptions of feeling emotionally re-connected and accepting after the treatment. The finding of a relationship between increased right amygdala responses to fearful neutral faces post treatment and subsequent clinical improvements adds further endorsement to this interpretation. Future work is required to test the replicability of these findings and test whether enhanced amygdala responsiveness is related to the potentially enduring positive mood effects of psychedelics. If confirmed, this would suggest an alternative neurobiological basis to the alleviation of depressive symptoms distinct from that of the SSRI antidepressants.
